Colleen Timlin

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Ibrutinib, a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase (BTK), is approved for chronic lymphocytic leukaemia (CLL) at a daily dose of 420 mg, which achieves ≥95% BTK occupancy (Advani et al, 2013; Byrd et al, 2013; Burger et al, 2015). Given that ibrutinib irreversibly binds to its target, the percentage of BTK saturation might have minimal contribution to drug efficacy, arguing that lower doses of ibrutinib might have comparable outcomes (Advani et al, 2013). To address this question, we conducted a multi-centre, retrospective analysis of CLL patients treated with ibrutinib below the US Food and Drug Administration-recommended starting dose. Our goal was to compare efficacy between the various dosing schedules. We conducted an Institutional Review Board-approved retrospective chart review of CLL patients treated with ibrutinib between January 2010 and October 2015 at three academic institutions. Demographics, ibrutinib dose, patient weight at start of ibrutinib, clinical responses, and survival outcomes were recorded. Reduced dose ibrutinib was defined as a sustained (≥2 months) dosing at <420 mg/day, either at treatment initiation or within 3 months from starting therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by the Kaplan–Meier method and stratified by ibrutinib dose (standard dose versus reduced dose) (Bland & Altman, 1998). PFS was defined by the time from initiation of therapy to the time of documented Cll progression, transformation, death or last follow up. Responses were defined according to modified 2008 response criteria (Hallek et al, 2008; Cheson et al, 2012). The log rank (LR) test and COX regression analyses were used to compare differences between Kaplan–Meier curves (Matthews & Farewell, 2007). All tests were 2-sided at the 5% level. Statistical analyses were performed using Stata version 10·1 (Stata Statistical Software: Release 10. College Station, TX, USA: StataCorp LP). We identified 197 ibrutinib-treated CLL patients (81% with relapsed-refractory disease; 19% front line). Thirty-seven patients (19%) received reduced dose ibrutinib. Median age for the entire cohort was 66 years, 3% received concomitant CYP3A4 inhibitor and 2% were treated with concomitant proton pump inhibitor. No significant differences in baseline characteristics between the standard-dose and reduced dose cohorts were observed. Fig 1 depicts weight based dosing of ibrutinib stratified by dose cohort. Of note, for the reduced dose patients the median ibrutinib dose was 4·3 mg/kg/day (4% <2·5 mg/kg/day). The most common reasons for ibrutinib dose reduction were gastrointestinal toxicity (16%), bleeding (11%), pharmacokinetic considerations (11%), rash (8%), cardiotoxicity (8%) and physician preference (46%). Only 5% of patients in the reduced dose group were concomitantly receiving a mild-moderate CYP3A4 inhibitor. Responses were not significantly different between the cohorts when stratified by dose (Fig 2A). The overall response rate, including partial response with lymphocytosis, for the standard-dose cohort was 85%, vs. 84% in the reduced dose group. The median PFS for the standard dose and reduced dose cohorts were 37·4 months and not reached, respectively (P = 0·6, LR test, Fig 2B). The median OS for standard dose and reduced dose cohorts were not reached (P = 0·5, LR test, Fig 2C). In Cox regression univariate analyses, ibrutinib dose (standard dose versus reduced dose) did not impact PFS [1·2, 95% confidence interval (CI) 0·5–2·6) or OS (0·6, 95% CI 0·14–2·7). To our knowledge, this report describes the largest real-world experience of reduced dose ibrutinib in CLL patients. While Barr et al (2015) demonstrated that prolonged ibrutinib dose interruptions may impact outcomes, these data demonstrate for the first time that ibrutinib dose reduction may not affect clinical outcomes. While this is a retrospective analysis and follow-up is limited, it provides reassurance to oncologists and patients when a dose reduction is indicated clinically. It also argues that weight-based dosing and pharmacoeconomic analyses should be considered in future studies. Moreover, consideration for comparative dosing studies that might have cost-savings and economic benefit should be seriously entertained. Joseph and Cindy Riggs. AM Designed research, performed research, analysed data, wrote the paper. CT Designed research, performed research, analysed data, wrote the paper. APS Performed research, wrote/edited the paper. CN Performed research, wrote/edited the paper. CU Performed research, wrote/edited the paper. CH Performed research, wrote/edited the paper. CH Performed research, wrote/edited the paper. SJS Performed research, wrote/edited the paper. Mato: Gilead: Consultancy, Research Funding; AbbVie:Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, TG Therapeutics: Research Funding; Acerta: Research Funding. Timlin: No conflicts of interest. Nabhan: Celgene Corporation:Honoraria, Research Funding. Skarbnik: Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Howlett: Teva: Speakers Bureau. Banerjee: No conflicts of interest. Schuster: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding;Genentech: Consultancy; Gilead: Research Funding; Hoffman-LaRoche:Research Funding; Celgene: Consultancy, Research Funding; Phamacyclics:Consultancy, Research Funding.